Major depression affects more than 10 percent of the US population. There are several treatment options available, but many individuals do not respond to therapy, medication or both. Despite agreement that neurotransmitters such as serotonin are important, it is clear that the mechanisms contributing to depression are considerably more complex than a simple deficit of serotonin function. One important feature of depression is that women are almost twice as likely as men to be affected by depression. Anxiety disorders are also more prevalent in women. For a variety of reasons however, most animal models examining neurobiological mechanisms related to depression focus on males. Indeed, there is an urgent need for the development of model systems in which behaviors related to depression and anxiety can be studied in both sexes (Wizemann and Pardue 2001). The chronic mild stress procedure can be applied in both male and female rodents, and this paradigm induces anhedonia (loss of interest in a rewarding stimulus). However, some laboratories have reported difficulty in replicating the effects of chronic mild stress on behavior. In contrast, the social stress (subordination) paradigm produces repeatable results in laboratory groups around the world. Social stress induces pronounced behavioral changes including anhedonia and a marked increase in social avoidance (or withdrawal). The behavioral effects of social stress are reversed by chronic, but not acute, antidepressant treatment. This is relevant because chronic, but not acute antidepressant treatment is effective in treating affective disorders in humans. The overwhelming majority of studies using social stress have focused on males. This is because in most species of rodents, female aggression is minimal, so it is difficult to create social stress using intra-female aggression. In contrast, female California mice (Peromyscus californicus) are aggressive, as males and females defend territories. In addition, preliminary data show that females have larger corticosterone responses than males during resident-intruder aggression tests. Insights into idiopathic depression, we expect it will be useful for testing mechanistic. Although our model may not provide hypotheses related to stress-induced depression. This application proposes to use the unique biology of the California mouse to examine sex differences in neurobiological mechanisms that mediate the effects of social stress on affective behaviors. PUBLIC HEALTH RELEVANCE: Affective disorders are more likely to occur in women, yet most mouse models focus on males in part due to logistical issues. We propose to use the social stress paradigm to examine social withdrawal and anhedonia in male and female California mice. We will examine the effects of social stress on behavior and expression of brain derived neurotrophic factor.